Novel anti-MM therapies are currently in clin. research, including CAR-T therapy, bispecific antibodies, and XPO1 inhibitors.XPO1 is a nuclear export protein that helps leucine-rich proteins transport from the nucleus to the cytoplasm.XPO1 is highly expressed in patients with MM and XPO1 overexpression is associated with short PFS and OS.These observations suggest that XPO1 has considerable value as a therapeutic target for patients with MM. Selinexor (KPT-330) was the first XPO1 inhibitor to be approved as a prescription drug for MM patients in 2019.Therefore, we designed and synthesized a novel XPO1 inhibitor, SZJK-0421, which structurally differs from selinexor.In this study, we tested the antiMM activity of SZJK-0421 in vivo and in vitro.Addnl., we compared the drug toxicity between SZJK-0421 and KPT-330.

Journal of Medicinal Chemistry

Discovery of SZJK-0421: A Novel Potent, Low Toxicity, Selective Second Generation of CRM1 Inhibitor for the Treatment of Both Hematological and Solid Tumors

Article

作者: Lei, Meng ; Qin, Yanru ; Wu, Ruokun ; Pan, Yupeng ; Chen, Qinghua ; Miao, Hang ; Shao, DingLu ; Ye, Xinran ; Wang, Xueyuan ; Zhu, Yongqiang

Nuclear export factor chromosome region maintenance 1 (CRM1) mediated the transport of various growth-regulatory proteins and was frequently overexpressed in many hematologic and solid tumors. Selinexor (KPT-330) was the only approved CRM1 inhibitor, but the severe gastrointestinal and central nervous system toxicities limited its clinical application. In this manuscript, a series of novel second-generation CRM1 inhibitors were designed, in which SZJK-0421 was a more reversible inhibitor than KPT-330. The treatment of various tumor cells with SZJK-0421 significantly inhibited the function of CRM1. SZJK-0421 displayed good liver microsome stabilities and pharmacokinetic properties. Most importantly, SZJK-0421 reduced the direct damage to the gastrointestinal mucosa, and the brain plasma distribution ratio of SZJK-0421 was very low in Sprague-Dawley (SD) rats (3%), which avoided gastrointestinal reactions such as central nausea and vomiting caused by large permeability of blood-brain barrier. In addition, SZJK-0421 exhibited strong anticancer efficacy in xenograft models of both solid and hematological tumors.

100 项与 SZJK-0421 相关的药物交易

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